Common, complex diseases constitute a major human heath burden. Rare genetic variants are an important component of disease risk and a full understanding of genetic architecture will require studies of hundreds of thousands - perhaps millions - of individuals. Study design, including ethnic diversity and pedigrees, and leveraging phenotypes proximal to the gene level will be critical for early success. Across three Discovery Projects, we will generate 50,000 whole genome sequences in well-phenotyped individuals to study disorders of the cardiovascular system, bone and metabolism. These projects will utilize Illumina HiSeq X instruments and the world-class analysis and informatics pipelines at Baylor College of Medicine's Human Genome Sequencing Center. Methods for investigating noncoding variation, including long-read haplotypes and structural variation, will be given particular attention throughout. The discovery projects will be followed by replication studies in even larger numbers, and a case-cohort strategy will aggregate these data as a prelude to a comprehensive experiment based on recruitment of patients via large health care networks. These prospective collections are a first step toward realizing precision medicine.